Emerging Procedures in Bariatric Metabolic Surgery.

Bariatric/metabolic surgery has emerged as an option for significant and durable weight loss in the treatment of clinically severe obesity; there is increasing demand for bariatric/metabolic surgery worldwide. New procedures have been developed and changed the face of modern bariatric surgery. Gastrointestinal metabolic surgery is a new treatment modality for obesity-related type 2 diabetes mellitus for patients with body mass index greater than 35 kg/m2. Providing safe bariatric/metabolic surgery, training qualified bariatric surgeons, and developing better techniques are important issues. This article discusses emerging procedures; a multitude of bariatric metabolic procedures enables surgeons to tailor treatment to patients' needs.

Banded Sleeve Gastrectomy and One Anastomosis Gastric Bypass/Mini-gastric Bypass for Treatment of Obesity: a Retrospective Cohort Comparative Study with 6 years follow-up.

BACKGROUND: Banded sleeve gastrectomy (BSG), a modification of the laparoscopic sleeve gastrectomy (SG), and one anastomotic gastric bypass/mini-gastric bypass (OAGB/MGB), a modification to the Roux-en-Y gastric bypass (RYGB), have been reported to enhance weight loss and minimize significant weight regain when compared with the SG and RYGB respectively. However, there has not been any report or study comparing these two operations. OBJECTIVE: We did a retrospective cohort study comparing these two operations and present a review and analysis with follow-up for 6 years. METHOD: A review of all the operations performed at MBRSC in 2011 from a prospectively maintained database was done. Patients who had either a BSG or OAGB/MGB were identified. Data on the patients' profile, co-morbid conditions, perioperative complications, late complications, weight loss, resolution of comorbidities, and changes in quality of life (QLF) were collected reviewed and analyzed. RESULT: Sixty-eight patients were identified who had a primary BSG and 55 who had an OAGB/MGB in 2011. The follow-up rate, the age, BMI, and gender composition were similar in both groups. There were more patients with type 2 diabetes (T2D) in the BSG group than in the OAGB/MGB group (44.1% vs. 27.2%). The incidences of hypertension (HTN) and obstructive sleep apnea (OSA) were higher in the OAGB/MGB group (62% vs. 36% and 96.3% vs. 2.9% respectively). The weight loss was faster in the OAGB/MGB group in the first year, but by the sixth year, the weight loss was slightly higher in the BSG group (84% vs. 79%). Resolution rate of T2D and HTN was higher after the OAGB/MGB group, 86.6% vs. 75.7% and 85.3% vs. 64.0% respectively. There was a 20% incidence of nutrient deficiencies in OAGB/MGB group and none in the BSG group. CONCLUSION: Both operations produced excellent weight loss and maintenance in the short to intermediate term. There was better resolution of T2D and HTN after OAGB/MGB at the expense of a higher incidence of nutrient deficiency and some protein caloric malnutrition. There is need for prospective and larger series studies to confirm these findings.

Use of a Systems Pharmacology Model Based Approach Toward Dose Optimization of Parathyroid Hormone Therapy in Hypoparathyroidism.

We present an application of a quantitative systems pharmacology (QSP) model to support a regulatory decision, specifically in assessing the adequacy of the proposed dosing regimen. On January 23, 2015, the US Food and Drug Administration (FDA) approved Natpara (human parathyroid hormone (PTH)) to control hypocalcemia in patients with hypoparathyroidism. Clinical trial results indicated that although once-daily PTH reduced calcium and vitamin D dose requirement while maintaining the normocalcemia, the regimen was not adequate to control hypercalciuria. We hypothesized that the lack of control on urinary calcium excretion was due to the short half-life of PTH. The QSP model-based simulations indicated that a more frequent dosing regimen may provide better control on hypercalciuria while maintaining normocalcemia. A postmarketing trial was recommended to assess pharmacokinetics (PKs) and pharmacodynamics (PDs) of PTH dose and dosing regimen. Although other modeling approaches may be feasible, in this specific case, QSP model-based simulations fulfilled the information gap to support recommendations of this postmarketing trial.

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization.

Canagliflozin (INVOKANA™) is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Canagliflozin inhibits renal sodium-glucose co-transporter 2 (SGLT2), thereby, reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Given the mechanism of action of SGLT2 inhibitors, we assessed the interplay between renal function, efficacy (HbA1c reduction), and safety (renal adverse reactions). The focus of this article is to highlight the FDA's quantitative clinical pharmacology analyses that were conducted to support the regulatory decision on dosing in patients with renal impairment (RI). The metrics for assessment of efficacy for T2DM drugs is standard; however, there is no standard method for evaluation of renal effects for diabetes drugs. Therefore, several analyses were conducted to assess the impact of canagliflozin on renal function (as measured by eGFR) based on available data. These analyses provided support for approval of canagliflozin in T2DM patients with baseline eGFR ≥ 45 mL/min/1.73 m(2) , highlighting a data-driven approach to dose optimization. The availability of a relatively rich safety dataset (ie, frequent and early measurements of laboratory markers) in the canagliflozin clinical development program enabled adequate assessment of benefit-risk balance in various patient subgroups based on renal function.

Dosing rationale for liraglutide in type 2 diabetes mellitus: a pharmacometric assessment.

The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide was approved in 2010 by the US Food and Drug Administration (FDA) as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. This article provides insights into the use of pharmacometric analyses for regulatory review with a focus on the dosing recommendations. The assessment was based on the totality of exploratory and confirmatory analysis of dose-finding and pivotal clinical data and was structured around a set of key questions in accordance with current FDA review practice. For the pharmacometric review of liraglutide, the key questions focused on exposure-response relationships for effects on fasting plasma glucose, hemoglobin A(1c), and calcitonin and on variability in exposure across demographic subgroups of patients. The importance of conducting exploratory exposure-response analysis and population pharmacokinetic studies in clinical drug development to support dosing recommendations is highlighted.

Characterization of total plasma glycosaminoglycan levels in healthy volunteers following oral administration of a novel antithrombotic odiparcil with aspirin or enoxaparin.

Odiparcil is a novel, orally active beta-d-thioxyloside analog with antithrombotic activity associated with a reduced risk of adverse bleeding events. Its unique mechanism of action is postulated by means of an elevation in circulating endogenous chondroitin sulfate-related glycosaminoglycans (GAGs) levels. The purpose of these 2 separate clinical studies was to evaluate plasma GAG levels in healthy subjects administered odiparcil with either aspirin (ASA) or enoxaparin. Clinical plasma samples were processed and analyzed using validated HPLC bioassays that indirectly estimate GAG levels based on the simultaneous detection of the chondroitin disaccharide derivatives. The concomitant administration of odiparcil with or without ASA resulted in a significant elevation in GAG levels over baseline for both treatment groups. In the other clinical study, the concomitant administration of odiparcil with or without enoxaparin displayed significant increases in plasma DeltaDi-OS, DeltaDi-4S, and total disaccharide levels versus control group. Neither plasma GAG levels nor odiparcil plasma levels were correlated with a rise in hepatic transaminases, an adverse drug event observed in several subjects; and plasma odiparcil levels were indirectly correlated with plasma GAG levels. These clinical studies were proof of concept of preclinical rat studies indicating that chronic odiparcil treatment elevates endogenous GAG levels in human subjects.

Determination of endogenous glycosaminoglycans derived disaccharides in human plasma by HPLC: validation and application in a clinical study.

SB-424323 is a new, orally active anti-thrombotic agent presently in phase-II clinical development, with limited hemorrhagic risk and a unique mechanism of action involving the induction of glycosaminoglycans (GAGs) biosynthesis. The objective of the present study was to develop a simple and rapid high performance liquid chromatography (HPLC) method for determination of endogenous GAGs derived disaccharides in plasma samples from a phase-II clinical study of SB-424323. Sample preparation was a simple heat treatment of the diluted plasma followed by digestion of endogenous GAGs with chondroitinase ABC to yield unsaturated disaccharides, 2-acetamido-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-D-galactose (DeltaDi-0S), 2-acetamido-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-4-O-sulfo-D-galactose (DeltaDi-4S), and 2-acetamido-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-6-O-sulfo-D-galactose (DeltaDi-6S). These disaccharides were recovered and purified using centrifugal filtration through a filter with 3000 molecular weight cut-off along with externally added internal standard 2-acetamido-2-deoxy-3-O-(2-O-sulfo-beta-D-gluco-4-enepyranosyluronic acid)-D-galactose (DeltaDi-UA2S). A gradient reverse phase HPLC separation was developed on a Waters Symmetry C(18) column (4.6 mm x 150 mm, 5 microm) with a gradient mobile phase system consisting of 0.8 mM tetrabutylammonium hydrogen sulfate and 2mM sodium chloride and acetonitrile at a flow rate of 1.0 mL/min. The eluate was monitored with an ultraviolet detector set at 230 nm. Plasma standard curves were linear (r(2)> or =0.994) in the concentration range 1.0-20 microg/mL with a lower limit of quantification (LLOQ) of 1.0 microg/mL for each of the disaccharide. The mean measured quality control (QC) concentrations for the disaccharides deviated from the nominal concentrations in the range of -8.92 to 5.61% and -16.3 to 16.7%, for inter and intra-day, respectively. The inter and intra-day precision in the measurement of QC samples, were in the range of 3.21 to 18.2% relative standard deviation (R.S.D.) and 0.32 to 20.9% R.S.D., respectively. The inter and intra-day precision in the measurement of endogenous GAGs derived disaccharides in human control plasma, were in the range of 5.8 to 15.9% R.S.D. and 1.17 to 7.74% R.S.D., respectively. Stability of the processed samples was confirmed up to 48 h in the auto-sampler. The method is simple, reliable, and easily adaptable to analysis of large number of samples under logistics of a clinical study. The present method has been used to investigate the GAGs levels in the plasma of patients in a phase II clinical study of SB-424323.

Preclinical evaluation of the pharmacokinetics, brain uptake and metabolism of E121, an antiepileptic enaminone ester, in rats.

The present study describes the brain uptake, pharmacokinetics and metabolism of an anticonvulsant enaminone ester E121, which belongs to a new and active series of compounds with potential in vivo anticonvulsant activity in rodent models, in rats. A single dose of E121 was administered i.p. to male Sprague Dawley rats at 10 mg E121/kg body weight. Cohorts of animals (n=3) were killed at varying times over 0-24 h to collect plasma and brain samples. Urinary excretion of E121 was studied in a separate group of five rats at the same dose. A validated HPLC method was used to quantify E121 and its metabolites in plasma, brain and urine. LC-MS/MS was used to characterize the metabolites. The plasma and brain Cmax of 11.0+/-3.0 mg/l and 10.4+/-1.4 mg/kg, respectively, were observed for E121 at 15 min post dose and they declined in a mono-exponential fashion. The plasma Cl/F and t1/2 were 0.57 l/h/kg and 0.75 h, respectively. The brain uptake ratio of E121 was 0.9. Mass spectral analysis of urine showed two major metabolites (m/z 280) and one minor metabolite (m/z 236) that were consistent with initial hydrolysis of the compound to the acid followed by further decarboxylation and appears to be the major route of elimination of E121. The rapid and moderate brain uptake of E121 correlates well with its potential anticonvulsant activity (ED50 3.0 mg/kg p.o. in rats). The brain uptake, pharmacokinetic and metabolic profile of E121 supports the need to further evaluate this compound for its potential as an antiepileptic.

Pharmacokinetic interaction of tetracycline with centchroman in healthy female volunteers.

OBJECTIVES: We aimed to investigate the effect of tetracycline coadministration, with and without lactic acid bacillus spores supplementation, on the pharmacokinetics of centchroman, a nonsteroidal oral contraceptive, in healthy female volunteers. PARTICIPANTS AND METHODS: The study was a single-centre, single-blinded, randomised, parallel treatment study in healthy female subjects of reproductive age randomised to two groups (11 subjects in each group). On day 1, subjects were given either a single oral dose of centchroman 30 mg with tetracycline 250 mg (group A) or a single dose of centchroman 30 mg, tetracycline 250 mg and one tablet containing 60 million lactic acid bacillus spores (group B). Tetracycline (250 mg three times daily) and lactic acid bacillus spores (one tablet three times daily) were continued for 3 days. Serial blood samples were collected and analysed by high performance liquid chromatography. The pharmacokinetic parameters were compared with the control data reported previously from this laboratory. RESULTS: Coadministration of tetracycline yielded significantly higher maximum plasma concentrations (C(max)) [35%] and a shorter time to reach C(max) (t(max)) values for centchroman (42%) than those obtained in the control group of females (p < 0.05). Inclusion of lactic acid bacillus spores in the regimen resulted in similar effects with increased C(max) (47%) and area under the concentration-time curve from time zero to infinity (34%) of centchroman (p < 0.05) with a significant decrease in t(max). Other parameters such as half-life, apparent clearance, apparent volume of distribution and mean residence time of centchroman were not affected by either of the treatments. CONCLUSIONS: The apparent effects of either of the regimens on centchroman pharmacokinetics seem to be of little clinical relevance in terms of increased rate or extent of availability. It can be concluded that this tetracycline-containing regimen is unlikely to alter the contraceptive efficacy of centchroman in humans.

Synthesis and anticonvulsant activity of enaminones. Part 7. Synthesis and anticonvulsant evaluation of ethyl 4-[(substituted phenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylates and their corresponding 5-methylcyclohex-2-enone derivatives.

Further investigation of the potential anticonvulsant activity of the enaminones was attempted to discern the possible role of metabolites as the active/co-active entities of the esters of the enaminones. A series of 5-methyl-2-cyclohexene enaminones, the hypothesised metabolites corresponding to a sequence of active and inactive esters were synthesised and evaluated for anticonvulsant activity. With two exceptions, ethyl 4-[(4-cyanophenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylate (1k), and 3-[N-(4-cyanophenyl)amino]-5-methyl-2-cyclohexenone (3g), and ethyl 4-(phenylamino)-6-methyl-2-cyclohexenone (1n), and 3-N-(phenylamino)-5-methyl-2-cyclohexenone (3j), anticonvulsant screening data were parallel, with the ester and their putative decarboxylated analogue displaying similar activity. The most active analogue evaluated in this series, ethyl 4-[(4-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylate (1e), which displayed an ED(50) of 16.7 mg kg(-1) and a TD(50) of 110.7 mg kg(-1) (protective index, PI = TD(50)/ED(50) = 6.6) in the maximal electroshock seizure (MES) test in mice and an ED(50) of 3.0 mg kg(-1) and a TD(50) >250 mg kg(-1) (PI > 83.3) in rats in the same evaluation, making this compound the most potent enaminone emanating from our laboratories. Pharmacokinetic evaluation of compound 1e in rats using LC/MS analysis unequivocally provides evidence that this compound is converted into the decarboxylated analogue 3a in the brain and the urine.